Outcomes of steroid-resistant nephrotic syndrome in children not treated with intensified immunosuppression.

BACKGROUND: The aim of the current PodoNet registry analysis was to evaluate the outcome of steroid-resistant nephrotic syndrome (SRNS) in children who were not treated with intensified immunosuppression (IIS), focusing on the potential for spontaneous remission and the role of angiotensin blockade on proteinuria reduction. METHODS: Ninety-five pediatric patients who did not receive any IIS were identified in the PodoNet Registry. Competing risk analyses were performed on 67 patients with nephrotic-range proteinuria at disease onset to explore the cumulative rates of complete or partial remission or progression to kidney failure, stratified by underlying etiology (genetic vs. non-genetic SRNS). In addition, Cox proportional hazard analysis was performed to identify factors predicting proteinuria remission. RESULTS: Eighteen of 31 (58.1%) patients with non-genetic SRNS achieved complete remission without IIS, with a cumulative likelihood of 46.2% at 1 year and 57.7% at 2 years. Remission was sustained in 11 children, and only two progressed to kidney failure. In the genetic subgroup (n = 27), complete resolution of proteinuria occurred very rarely and was never sustained; 6 (21.7%) children progressed to kidney failure at 3 years. Almost all children (96.8%) received proteinuria-lowering renin-angiotensin-aldosterone system (RAAS) antagonist treatment. On antiproteinuric treatment, partial remission was achieved in 7 of 31 (22.6%) children with non-genetic SRNS and 9 of 27 children (33.3%) with genetic SRNS. CONCLUSION: Our results demonstrate that spontaneous complete remission can occur in a substantial fraction of children with non-genetic SRNS and milder clinical phenotype. RAAS blockade increases the likelihood of partial remission of proteinuria in all forms of SRNS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term outcome of early steroid withdrawal in pediatric renal transplantation.

BACKGROUND: Steroid use in renal transplant is related to multiple adverse effects. Long-term effects of early withdrawal steroids in pediatric renal transplant were assessed. METHODS: Renal transplant children with low immunological risk treated on basiliximab, tacrolimus, and mycophenolate with steroid withdrawal or steroid control were evaluated between 2003 and 2019. Clinical variables, treatment adherence, acute rejection, graft loss, and death were analyzed through hazard ratios, and Kaplan-Meier and multivariate analyses. RESULTS: The study included 152 patients, 71.1% steroid withdrawal, mean follow-up 8.5 years, 64.5% structural abnormalities, and 81.6% deceased donor. At 12 years of transplant, event-free survival analysis for graft loss or death showed no significant difference between steroid withdrawal and control steroid treatment (85.9% vs. 80.4%, p = .36) nor in acute rejection at 10 years (18.5% vs. 20.5%, p = .78) or in donor-specific antibody appearance (19.6% vs. 21.4%, p = .98). Delta height Z-score was increased in the steroid withdrawal group (p < .01). The main predictor of graft loss or death was non-adherence to treatment (p = .001; OR: 17.5 [3.3-90.9]). CONCLUSIONS: Steroid withdrawal therapy was effective and safe for low-risk pediatric renal transplant in long-term evaluation. Non-adherence was the main predictor of graft loss or death.

Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.

Impaired phosphorylation of JAK2-STAT5b signaling in fibroblasts from uremic children.

BACKGROUND: Chronic kidney disease (CKD) in children is characterized by severe growth failure. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in uremic animals shows a post-receptor impaired phosphorylation of Janus kinase 2/signal transducer and activator of transcription (JAK-STAT) proteins. The objective of our study was to characterize the intracellular phosphorylation of JAK-STAT signaling in fibroblasts from children with CKD on chronic peritoneal dialysis (PD). METHODS: Serum GH-binding protein (GHBP), IGF-1 and IGFBP3 were measured in 15 prepubertal CKD stage-5 children on PD. Cytoplasmic JAK2, cytoplasmic/nuclear STAT5b and nuclear IGFBP3, acid-labile subunit (ALS) and IGF-1 mRNA expression were quantified in fibroblasts obtained from skin biopsies before and after stimulation with 200 ng/ml recombinant human growth hormone (rhGH). Phosphorylation activity at both the cytoplasmic and nuclear level was expressed as the ratio phosphorylated (p)/total (t) abundance of the product (p/t) at 30 and 60 min. Fifteen healthy children were recruited as the control group. Values were expressed in arbitrary units (AU) and normalized for comparison. Significance was defined as p < 0.05. RESULTS: Thirty minutes after rhGH stimulus, the cytoplasmic (p/t) JAK2 ratio was significantly lower in patients than in controls [median and interquartile range (IQR): 7.4 (4.56) vs. 20.5 (50.06) AU]. At 60 min after rhGH stimulation, median JAK2 phosphorylation activity was still significantly lower in the patients [7.14 (IQR 3.8) vs. 10.2 (IQR 29.8) AU; p < 0.05]. The increase in the cytoplasmic (p/t) STAT5b/ß-actin ratio was lower at both measurement points in the patients compared to the controls, without reaching statistical significance between groups. Median IGFBP3 mRNA abundance was significantly decreased in fibroblasts from uremic patients 24 h after rhGH stimulation compared to the healthy controls [1.27 (IQR 0.83) vs. 2.37 (IQR 0.80) AU]. Median ALS and IGF-1 mRNA expression changed in response to rhGH stimuli at 24 and 48 h. CONCLUSION: In this study, children with CKD undergoing PD therapy showed an impaired phosphorylation of JAK2/STAT5b signaling in fibroblasts after GH stimulation, as well as impaired IGFBP3 mRNA abundance. Both impairments may be partially responsible for the observed resistance to the growth-promoting actions of GH in chronic kidney failure.

[NPHS2 Mutation analysis study in children with steroid-resistant nephrotic syndrome]. / Identificación de variantes del gen NPHS2 en niños con síndrome nefrótico corticorresistente.

UNLABELLED: Podocin is a protein located in the glomerular slit diaphragm where it takes part in the regulation of glomerular filtration. Mutations of the NPHS2 gene that codes podocin are the main cause of autosomal recessive steroid resistant nephrotic syndrome (SRNS). OBJECTIVES: To identify the NPHS2 mutations in Chilean children with SRNS, and to determine the prevalence of the most common variants in a group of healthy adults. PATIENTS AND METHODS: Mutation analysis of NPHS2 in 34 Chilean children with SRNS. Once the two most common variants of NPHS2 were identified, screening for these mutations was performed on 233 healthy adults. The mutation analysis was performed by the direct sequencing of the eight coding exons by polymerase chain reaction amplification. The DNA sequencing was performed using a fluorometric method, and then evaluated with SeqPilot software. The relationship between the presence of NPHS2 variants and SRNS was calculated by comparing the allele frequency between patients with SRNS and those of the healthy volunteers using the exact Fisher test. A P<.05 was considered significant. RESULTS: Pathogenic NPHS2 mutations were detected in 7 (21%) of the 34 patients studied, of which 6 were heterozygotes for p.R229Q and p.A284V. The presence of p.R229Q was 2.46% in the healthy volunteers. CONCLUSIONS: This study shows that p.R229Q and p.A284V are the most frequent variants in Chilean children with SRNS. It is the first time that this relationship has been reported in Chilean children. Based on this, a screening strategy is proposed for the genetic study in patients with SRNS and their families. A parallel or sequential search strategy for p.R229Q and p.A284V in these patients is proposed.

Genotype-phenotype associations in WT1 glomerulopathy.

WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome.

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

The mini-PET in pediatric peritoneal dialysis: a useful tool to predict volume overload?

BACKGROUND: Cardiovascular disease (CVD) in patients on chronic peritoneal dialysis (PD) is a major cause of death and is closely linked to hypertension and volume overload. The mini-Pet has been proposed as a useful tool to evaluate free-water transport (FWT) and characterize ultrafiltration across the peritoneum. Knowledge regarding FWT could be of great value to predict volume overload in PD patients. Our objective in this study was to characterize FWT through the peritoneum in children on PD. METHODS: We studied clinically stable patients with >2 months on PD. Exclusion criteria were a peritonitis episode up to 2 months prior to entrance into the study and active nephrotic syndrome. A 1-h mini-peritoneal equilibration test (mini-PET) was performed with 3.86 % glucose. Calculations (see text for full definitions) were: Dip Na (Na dial min60 - Na dial min1), Dip D/PNa (D/PNa60 - D/PNa1), total Na removal (NaR = total Na dial60 - Na dial1), ultrafiltration small pores [(UFSP = NaR × 1,000)/Nap], and FWT (UF-UFSP). Peritoneal equilibration test (PET), left ventricular mass index (LVMI, g/m(2)), daily UF, and residual renal function were evaluated. Pearson's correlation coefficient was used to establish correlation between variables. RESULTS: Sixteen patients were included, with a mean age of 11.8 ± 3.8 years. Free water transport normalized to body surface area (BSA) (FWTn) was 133.9 ± 85.7 ml/m(2); creatinine dialysate-to-plasma (D/P) and glucose dialysate at X dwell time-to-0 dwell time (Dx/D0) ratios were 0.38 ± 0.1 and 0.65 ± 0.09, respectively. LVMI was 46.6 ± 14.8 g/m(2); 2-h creatinine D/P and glucose Dx/D0 showed no correlation with FWTn, UF, and LVMI. FWTn showed a significant inverse correlation with LVMI (r 0.58, p 0.02). CONCLUSIONS: This study characterized FWT in PD children through the mini-PET. Left ventricular hypertrophy showed a high prevalence in this group, and a significant correlation between LVMI and FWT was found. FWT could be a useful tool to evaluate UF in PD children.

Growth in very young children undergoing chronic peritoneal dialysis.

Very young children with chronic kidney disease often have difficulty maintaining adequate nutrition, which contributes to the high prevalence of short stature in this population. Characteristics of the dialysis prescription and supplemental feeding via a nasogastric (NG) tube or gastrostomy may improve growth, but this is not well understood. Here, we analyzed data from 153 children in 18 countries who commenced chronic peritoneal dialysis at <24 months of age. From diagnosis to last observation, 57 patients were fed on demand, 54 by NG tube, and 10 by gastrostomy; 26 switched from NG to gastrostomy; and 6 returned from NG to demand feeding. North American and European centers accounted for nearly all feeding by gastrostomy. Standardized body mass index (BMI) uniformly decreased during periods of demand feeding and increased during NG and gastrostomy feeding. Changes in BMI demonstrated significant regional variation: 26% of North American children were obese and 50% of Turkish children were malnourished at last observation (P < 0.005). Body length decreased sharply during the first 6 to 12 months of life and then tended to stabilize. Time fed by gastrostomy significantly associated with higher lengths over time (P < 0.001), but adjustment for baseline length attenuated this effect. In addition, the use of biocompatible peritoneal dialysate and administration of growth hormone independently associated with improved length, even after adjusting for regional factors. In summary, growth and nutritional status vary regionally in very young children treated with chronic peritoneal dialysis. The use of gastrostomy feeding, biocompatible dialysis fluid, and growth hormone therapy associate with improved linear growth.

Growth of kidney-transplanted pediatric patients treated with sirolimus.

Experimental findings indicate that sirolimus (SRL) inhibits longitudinal growth by mechanisms potentially related to its inhibitory effects on both cell proliferation and expression of vascular endothelial growth factor (VEGF). The aim of this study was to investigate the growth pattern of kidney-transplanted children treated with SRL in a multicenter observational clinical study. Height, change in height SD (Δ height) and growth velocity of pediatric patients with renal transplant were calculated at 0, 6, 12, and 24 months after starting SRL. Controls of kidney-transplanted children not treated with SRL were matched by age, gender, renal function, and dose of corticosteroids. Sixty-eight children (34 SRL, 34 controls) were enrolled in the study. Nephrotoxicity was the most frequent indication to start therapy with SRL. SRL exerted an adverse effect on growth as demonstrated by significantly lower (p < 0.05) growth velocity (cm/year) and smaller change in height SD in the SRL group after 6 (4.08 vs. 6.56 and -0.05 vs. 0.14), 12 (4.44 vs. 6.11 and -0.03 vs. 0.28) and 24 (4.53 vs. 6.03 and -0.04 vs. 0.53) months of treatment. This study suggests that SRL therapy may interfere with growth of kidney-transplanted children. This undesirable effect needs to be taken into account when considering a switch to SRL and confirmed in further prospective trials including larger number of patients.

Continuous EPO receptor activator therapy of anemia in children under peritoneal dialysis.

The short half-life of erythropoietin (rHuEPO) leads to repeated fluctuations in hemoglobin levels and the need for frequent administration. Continuous erythropoietin receptor activator (CERA) therapy has been approved for once or twice a month in adult dialysis patients. To evaluate the efficacy and safety of CERA therapy in the management of anemia in pediatric peritoneal dialysis (PD) stable PD children under twice-a-week EPO were converted to a subcutaneous CERA, scheduled every 2 weeks. The follow-up was 6 months. The primary efficacy parameter was hemoglobin > 11 g/dL. The exclusion criteria were ferritin <100 ng/ml and Hb saturation <20%. Sixteen children, aged 9.75 ± 3.6 years, including 11 boys, participated in the study. Mean Hb level at month 0 was 10.8 ± 1.9 g/dL. A decrease in hemoglobin to 10.38 ± 1 g/dL at month 2 was observed. The CERA dose was increased from 0.86 ± 0.33 to 1.67 ± 0.4 µg/kg at month 3. The target Hb level was reached by the 3rd month. The Hb level and CERA dose were 12.2 ± 1.2 and 1.6 ± 0.67 µg/kg respectively at the end of the study. No adverse events were observed during the protocol. CERA is an effective and safe therapy for maintaining hemoglobin levels when administered twice, up to once a month, in PD children. Doses required to reach target Hb were higher than published experiences in adult populations.

Early steroid withdrawal in pediatric renal transplant: five years of follow-up.

This prospective, comparative trial investigated the impact on mean change in height standard deviation score (SDS), acute rejection rate, and renal function of early steroid withdrawal in 96 recipients with 5 years of follow-up. Recipients under basiliximab induction and steroid withdrawal (SW: TAC/MMF; n = 55) were compared with a matched steroid control group (SC: TAC/MMF/STEROID, n = 41). SW received steroids until Day 6, SC decreased to 10 mg/m(2) within 2 months post-transplant. Five years after SW, the longitudinal growth (SDS) gain was 1.4 ± 0.4 vs. 1.1 ± 0.3 for SC group (p < 0.02). Height benefits in prepubertal and pubertal status in both groups were demonstrated in the delta growth trends (mixed model; p < 0.01). Biopsy-proven acute rejection in SW was 11% and 17.5%, SC (p: ns). Mean eGFR (ml/min/1.73 m(2)) at 5 years post-transplant was SW 80.6 ± 27.8 vs. 82.6 ± 25.1 for SC (p: ns). The death-censored graft survival rate at 1 and 5 years was 99 and 90% for SW; 98 and 96% for SC (p = ns). PTLD incidence in SW 3.3 vs. 2.5% in SC (p: ns). Five years post-transplant, early steroid withdrawal showed positive impacts on growth, stable renal function without increased acute rejection risk, and PTLD incidence.

[Hypovitaminosis D in pediatric patients on renal replacement therapy]. / Hipovitaminosis D en pacientes pediátricos en terapia de sustitución renal.

BACKGROUND: Hypovitaminosis D has a high prevalence among patients with chronic kidney disease (CKD). AIM: To determine the prevalence of 25 hydroxy vitamin D (25(OH) D) insufficiency and deficiency in pediatric patients on dialysis and kidney transplantation. MATERIAL AND METHODS: Serum calcium and phosphorus, parathormone (PTH), alkaline phosphatases and 25 (OH)D were measured in 13 children on hemodialysis (HD), 18 on peritoneal dialysis (PD) and 53 that received an allograft (Tx), aged 9.8 ± 4.6 years (51% females). RESULTS: Fifty four percent of patients had height Z score less than -1.88. Patients on HD had the lowest values. The average time of replacement therapy was 2.9 ± 2.8 years. Mean 25(OH)D levels in all was 18.7 ± 10.7ng/ml (HD: 21 ± 16.8, PD: 18.9 ± 8.5, Tx: 18.1 ± 9.72 ng/ml). Eighty eight percent of patients had levels below 30 ng/ml. Mean of serum calcium was 9.5 ± 0.64 mg/dl, serum phosphorus 5.03 ± 1.02 mg/dl, calcium-phosphorus product 48 ± 11.8 mg/dl and alkaline phosphatases 300.5 ± 171.3 IU/L. Average PTH values in dialyzed and Tx patients were 724.6 ± 640.5 and 107.7 ± 56.2 pg/ml, respectively (p < 0.001). A positive correlation between 25 (OH) D and calcium levels among PD patients was observed (r = 0.490, p = 0.04). CONCLUSIONS: Hypovitaminosis D is highly prevalent among children on renal substitution therapy, regardless of the type of therapy used and the stage of renal failure.

[Type 1 diabetes mellitus and Graves Basedow's disease, a case of Autoimmune Polyglandular Syndrome]. / Diabetes mellitus tipo 1 y enfermedad de Graves Basedow, un caso de Síndrome Poliglandular Autoinmune.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is one of the most frequent autoimmune diseases in childhood. Its diagnosis requires the search for other autoimmune diseases. OBJECTIVE: to present the case of a pediatric patient with two rare concomitant autoimmune endocrine diseases. CLINICAL CASE: A 12-year-old male with no significant morbid history, is hospitalized due to a 3-month clinical pic ture of fatigue, eye pain, intermittent eyelid edema, goiter, polyphagia, polydipsia, polyuria, and weight loss (12 kilograms), compatible with T1DM and Graves-Basedow disease. It was confir med by laboratory tests which showed elevated glycemia (207 mg/dL, HbA1C 10.9%), suppressed TSH (< 0.01 uIU/mL), elevated FT4 (6.99 ng/dL), and the presence of anti-autoantibodies thyroid peroxidase, antithyroglobulin, and anti-TSH receptor, along with suggestive ultrasound findings. Therefore, we established the diagnosis of autoimmune polyglandular syndrome (APS) 3A and initiated treatment with insulin, propranolol, and thiamazole. The patient evolved satisfactorily and was discharged with outpatient follow-up. CONCLUSION: We present the case of an adolescent who presented APS due to T1DM and hyperthyroidism. This APS may be more common than is reported in clinical practice. The alteration of two or more endocrine glands or other autoimmune diseases should make us suspect its diagnosis, with important clinical implications, such as co morbidity and quality of life prognosis.

The short peritoneal equilibration test in pediatric peritoneal dialysis.

The peritoneal equilibration test (PET) is the gold standard method for defining peritoneal membrane permeability and for prescribing peritoneal dialysis (PD) therapy on an individual basis. However, it is laborious, consumes nursing time, and requires many hours to be performed. Therefore, several authors have attempted to validate a short PET protocol, with controversial results. To evaluate the concordance between the 2-h (short) and 4-h (classical) peritoneal equilibrium test, a prospective observational protocol was applied in three PD centers (Mexico, Chile, and Uruguay) between July 1, 2008 and July 31 2009. PET protocol: the night prior to the test, each patient received five exchanges, 1 h each, at the same glucose concentration as previously used. Afterwards, a 2.5% glucose dialysis solution was used for a dwell time of 4 h. Exchange fill volume was 1,100 ml/m2 body surface area. The next morning, the 4-h dwell was drained, and Dianeal 2.5% was infused. Three dialysate samples at 0, 2, and 4 h were obtained. A single blood sample was obtained at 120 min. Creatinine D/P and glucose D/D0 ratios were calculated at hours 0, 2, and 4. Patients were categorized as low, low average, high average, or high transporters according creat D/P and gluc D/D0 results. Pearson and Kappa test were used for numerical and categorical correlations, respectively, and p<0.05 was considered significant. Eighty-seven PET studies were evaluated in 74 patients, 33 males, age 11.1+/-5.05 years old. A positive linear correlation of 92% between 2 and 4-h creat D/P and 80% between 2 and 4-h gluc D/D0 (p<0.001) was founded. The Kappa test showed a significant concordance between creat D/P and gluc D/D0 categories at 2 and 4 h (p<0.001). When analyzing cut-off-value categories, creat D/P was founded to be lower and gluc D/D0 higher than other experiences. This multicentric prospective study strongly suggests that PET obtained at 2 h and 4 h, based on either creatinine or glucose transport, provides identical characterization of peritoneal membrane transport capacity in PD children.

Intraperitoneal calcitriol in infants on peritoneal dialysis.

BACKGROUND: Calcitriol has long been used as the main therapy in renal osteodystrophy, but the efficacy of the oral route is not always as high as expected. OBJECTIVE: To asses the safety and efficacy of intraperitoneal calcitriol in infants undergoing peritoneal dialysis (PD). PATIENTS AND METHODS: PD patients on oral calcitriol therapy, with serum parathyroid hormone (PTH) >1000 pg/mL during the previous 3 months of treatment, were switched to intraperitoneal calcitriol therapy, 1 microg twice per week. Dose was increased to 1 microg three times per week if PTH remained >1000 pg/mL, and was later readjusted. Target PTH was 200-300 pg/mL according DOQI guidelines. STATISTICS: All results are expressed as mean +/- SE. The Wilcoxon signed rank test was used to evaluate differences in measurements for each pair of values. The confidence interval for differences between population medians was 96.9%. A p value less than 0.05 was considered significant. RESULTS: Six male children, mean age 17 +/- 3.86 months, completed a 12-month follow-up. Mean pretreatment PTH was 1654 +/- 209 pg/mL. Mean PTH at months 0, 3, 6, 9, and 12 was 1448 +/- 439*, 1277 +/- 723, 910 +/- 704, 582 +/- 282*, and 465 +/- 224* pg/mL, respectively (*p < 0.05). Twelve hypercalcemic and 10 hyperphosphatemic episodes were successfully treated. CONCLUSION: Infants on PD who fail to respond to oral calcitriol therapy can be safely treated with intraperitoneal administration of active vitamin D.

Peritoneal Dialysis Access Revision in Children: Causes, Interventions, and Outcomes.

BACKGROUND AND OBJECTIVES: Little published information is available about access failure in children undergoing chronic peritoneal dialysis. Our objectives were to evaluate frequency, risk factors, interventions, and outcome of peritoneal dialysis access revision. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were derived from 824 incident and 1629 prevalent patients from 105 pediatric nephrology centers enrolled in the International Pediatric Peritoneal Dialysis Network Registry between 2007 and 2015. RESULTS: In total, 452 access revisions were recorded in 321 (13%) of 2453 patients over 3134 patient-years of follow-up, resulting in an overall access revision rate of 0.14 per treatment year. Among 824 incident patients, 186 (22.6%) underwent 188 access revisions over 1066 patient-years, yielding an access revision rate of 0.17 per treatment year; 83% of access revisions in incident patients were reported within the first year of peritoneal dialysis treatment. Catheter survival rates in incident patients were 84%, 80%, 77%, and 73% at 12, 24, 36, and 48 months, respectively. By multivariate logistic regression analysis, risk of access revision was associated with younger age (odds ratio, 0.93; 95% confidence interval, 0.92 to 0.95; P<0.001), diagnosis of congenital anomalies of the kidney and urinary tract (odds ratio, 1.28; 95% confidence interval, 1.03 to 1.59; P=0.02), coexisting ostomies (odds ratio, 1.42; 95% confidence interval, 1.07 to 1.87; P=0.01), presence of swan neck tunnel with curled intraperitoneal portion (odds ratio, 1.30; 95% confidence interval, 1.04 to 1.63; P=0.02), and high gross national income (odds ratio, 1.10; 95% confidence interval, 1.02 to 1.19; P=0.01). Main reasons for access revisions included mechanical malfunction (60%), peritonitis (16%), exit site infection (12%), and leakage (6%). Need for access revision increased the risk of peritoneal dialysis technique failure or death (hazard ratio, 1.35; 95% confidence interval, 1.10 to 1.65; P=0.003). Access dysfunction due to mechanical causes doubled the risk of technique failure compared with infectious causes (hazard ratio, 1.95; 95% confidence interval, 1.20 to 2.30; P=0.03). CONCLUSIONS: Peritoneal dialysis catheter revisions are common in pediatric patients on peritoneal dialysis and complicate provision of chronic peritoneal dialysis. Attention to potentially modifiable risk factors by pediatric nephrologists and pediatric surgeons should be encouraged.

Total carnitine and acylated carnitine ratio: relationship of free carnitine with lipid parameters in pediatric dialysis patients.

Carnitine has an essential role in the mitochondrial oxidation of long-chain fatty acids. Carnitine deficiency has been described in patients with chronic kidney disease. Total carnitine (TC) deficiency or a lower-than-normal ratio of free carnitine to acylated carnitine (FC:AC) has been shown to be associated with disorders in metabolism and plasma lipids. Metabolism and therapeutic use of carnitine have therefore been a major area of interest in dialysis patients. In a prospective observational study, we determined carnitine status (TC and FC:AC) and its correlations with lipid plasma levels in peritoneal dialysis (PD) and hemodialysis (HD) patients. In pediatric patients on chronic PD or HD, we evaluated nutritional status (weight and height), biochemical parameters (TC, FC, and AC levels), and fasting plasma lipoprotein concentrations. We studied 35 patients (16 boys, 19 girls; 25 on PD, 10 on HD). Median age was 5 years (range: 3 months-15 years). Median weight-to-height Z-score was -0.5 (range: -2.1 to 1.9), and median height-to-age Z-score was -2.5 (range: -0.3 to -2.9). The mean TC was 65.4 +/- 23.8 pg/mL (normal value: 40-55 pg/mL); the median AC was 18 pg/mL (range: 2-56pg/mL; normal value: 3-15 pg/mL); and the mean FC was 41.8 +/- 16.6 pg/mL (normal value: 25-35 pg/mL). Median serum FC:AC was 2.22 (range: 0.59-4.3; normal value: 4). A significantly higher AC and a lower FC:AC were observed in HD patients as compared with PD patients. No differences in TC and FC were observed when patients were grouped by dialysis modality, time on dialysis, or nutrition status. Total cholesterol was 200 mg/dL or higher in 20 patients, and 25 patients showed elevated triglycerides (> 150 mg/dL). The latter patients had a higher AC than did the group of patients with triglycerides below 150 mg/dL (AC: 22 pg/mL and 12.5 pg/mL respectively; Kruskal-Wallis p < 0.003). We found TC levels to be high in this group of patients. However, the FC:AC ratio was lower than normal in all except in 1 patient. Elevated triglycerides were associated with elevated AC, suggesting carnitine insufficiency in our patients.

Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS: Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS: The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Body composition in children on peritoneal dialysis.

Dual-energy X-ray absorptiometry (DEXA) can be used to evaluate total-body bone mineral content (BMC), bone mineral density (BMD), fat-free mass (FFM), and fat body mass (FBM), which are all frequently affected in patients (PD) on peritoneal dialysis. We used DEXA to evaluate body composition in children on PD and to establish whether relationships existed with nutrition status, dialytic parameters, and biochemical data. We evaluated 20 PD patients (12 boys, 8 girls). The mean age of the patients was 5.84 years (range: 0.16- 14.66 years). We carried out DEXA, anthropometry (weight/age, height/age, and body mass index), and measurements of dietary intake (protein, energy, calcium, and phosphorus), nitrogen balance (NB), dialysis dose (Kt/V), peritoneal equilibrium test (PET), and plasma calcium, phosphorus, and bicarbonate at months 1 and 6 of the study. Energy intake was prescribed according to the United States Recommended Dietary Allowances, and Kt/V and daily protein intake (DPI) according to the Dialysis Outcomes Quality Initiative (DOQI) guidelines. In the patients, BMD increased to 0.769 +/- 0.174 g/ cm2 from 0.747 +/- 0.166 g/cm2 (p < 0.05), and BMC increased to 680.3 +/- 666.1 g from 632.6 +/- 597.5 g (p < 0.01). The mean BMD Z score for patients older than 4 years (n = 11) was -0.69 at month 1, with a significant increase to -0.35 at month 6. The FBM and FFM increased, but without reaching statistical significance. At months 1 and 6, the DPI was 144.3% and 129.9% respectively (p = nonsignificant) and showed a negative correlation with BMD, BMC, and FFM (p < 0.05). Comparing DPI to plasma bicarbonate showed a negative correlation at month 1 (p < 0.05). Negative correlations were also found between NB and the parameters BMD, FBM, and FFM (p < 0.05). be content All patients showed a positive NB. No correlation was found between DEXA and anthropometric measurements, energy intake, serum calcium, serum phosphorus, or Kt/V Dialysate-to-plasma creatinine from the PET showed a negative correlation with BMD and FFM (p < 0.05). In terms of positive NB and controlled Kt/V we observed an increase in bone mineralization within the 6 months offollow-up. A high protein intake seems to negatively affect acid-base status, bone mineralization, and FFM.